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Olfactomedin-4 Is a Candidate Marker for a Pathogenic Neutrophil Subset in Septic Shock

Alder, Matthew N. MD, PhD1,2; Opoka, Amy M. BS1; Lahni, Patrick BS1; Hildeman, David A. PhD1,3; Wong, Hector R. MD1,2

doi: 10.1097/CCM.0000000000002102
Online Laboratory Investigations
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Objectives: Heterogeneity in sepsis-related pathobiology presents a significant challenge. Resolving this heterogeneity presents an opportunity to understand pathobiology and improve patient care. Olfactomedin-4 is a neutrophil subset marker and may contribute to sepsis heterogeneity. Our objective was to evaluate the expression of olfactomedin-4 and characterize neutrophil heterogeneity in children with septic shock.

Design: Single-center, prospective cohort, as well as secondary analysis of existing transcriptomic and proteomic databases.

Setting: Tertiary care PICU.

Patients: Patients from 5 days to 18 years old with septic shock were enrolled. Data collected included the expression of olfactomedin-4 messenger RNA, serum protein concentrations, and percentage of neutrophils that express olfactomedin-4.

Interventions: None.

Measurements and Main Results: Secondary analysis of existing transcriptomic data demonstrated that olfactomedin-4 is the most highly expressed gene in nonsurvivors of pediatric septic shock, compared with survivors. Secondary analysis of an existing proteomic database corroborated these observations. In a prospectively enrolled cohort, we quantified the percentage of olfactomedin-4+ neutrophils in patients with septic shock. Patients with a complicated course, defined as greater than or equal to two organ failures at day 7 of septic shock or 28-day mortality, had a higher percentage of olfactomedin-4+ neutrophils, compared with those without a complicated course. By logistic regression, the percentage of olfactomedin-4+ neutrophils was independently associated with increased risk of a complicated course (odds ratio, 1.09; 95% CI, 1.01–1.17; p = 0.024).

Conclusions: Olfactomedin-4 identifies a subpopulation of neutrophils in patients with septic shock, and those with a high percentage of olfactomedin-4+ neutrophils are at higher risk for greater organ failure burden and death. Olfactomedin-4 might serve as a marker of a pathogenic neutrophil subset in patients with septic shock.

1Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Children’s Hospital Research Foundation, Cincinnati, OH.

2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

3Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Children’s Hospital Research Foundation, Cincinnati, OH.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by grant form National Institutes of Health K12 HD028827 (Dr. Alder), T32 GM008478 (Dr. Alder), R01GM099773 (Dr. Wong), and R01GM108025 (Dr. Wong).

Dr. Alder received support for article research from the National Institutes of Health (NIH). His institution received funding from the NIH. Dr. Lahni received support for article research from the NIH. Dr. Hildeman received support for article research from the NIH. Dr. Wong received support for article research from the NIH. His institution received funding from the NIH. Dr. Opoka has disclosed that she does not have any potential conflicts of interest.

For information regarding this article, E-mail: Matthew.alder@cchmc.org

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.